Process for treating lameness administration of a bisphosphonic acid derivative

ABSTRACT

The invention relates to a process for treating lameness with an osseous, articular or osteoarticular component, comprising the administration, to a human or to an animal not suffering from arthritis or from fractures, of an effective amount of a bisphosphonic acid derivative of formula:  
                 
 
     in which:  
     R 1  represents a hydrogen atom, a halogen atom, a hydroxyl, an amino, a mono(C 1 -C 4 )alkylamino or a di (C 1 -C 4 ) alkylamino;  
     R 2  represents a halogen atom, a linear alkyl comprising from 1 to 5 carbon atoms which is unsubstituted or substituted with a group chosen from a chlorine atom, a hydroxyl, an amino, a mono(C 1 -C 4 )alkylamino or a di (C 1 -C 4 )alkylamino; a (C 3 -C 7 ) cycloalkylamino,  
     or R 2  represents a phenoxy, a phenyl, a thiol, a phenylthio, a chlorophenylthio, a pyridyl, a pyridyl-methyl, a 1-pyridyl-1-hydroxymethyl, an imidazolyl-methyl or a 4-thiomorpholinyl,  
     of one of its pharmaceutically acceptable salts or of one of its hydrates.

[0001] The present invention relates to a process for treating lamenesswith an osseous, articular or osteoarticular component in human orveterinary medicine, comprising the administration of a bisphosphonicacid derivative.

[0002] The term lameness is understood to refer to irregular gait causedby the perception of a pain by partially or fully bearing weight on oneor more limbs during the functioning of limbs prompted into motion.

[0003] Lameness can manifest itself clinically in an intermittent orcontinuous manner for several days, several weeks or several months.

[0004] Lameness results more specifically from the appearance of painfullesions on the bone structure, the cartilages, the ligaments, thesynovial membrane or the connective tissue or from an anomaly of localvascularization. Thus, lameness is generally associated with one or moreof the following components:

[0005] an osseous component which is the result of a change in the bonearchitecture and/or in the bone growth cartilages at the site of thelameness, such as, for example, losses of bone substance, the formationof cysts, deformation of the bone or excessive thickening of the growthcartilages;

[0006] an articular component which is the result of a change in thestructure of the articular cartilages, such as, for example, erosions ofthe cartilaginous surfaces and/or a change in the synovial membraneand/or a change in the articular ligaments;

[0007] a muscular component which is the result of a change in muscledevelopment, such as, for example, a muscular atrophy; and

[0008] a vascular component which is the result of a change in localvascularization, such as, for example, a reduction in vascularization ofthe injured region.

[0009] The invention is directed towards providing a process fortreating lameness with an osseous component and/or with an articularcomponent which appear in a person or an animal not suffering fromfractures or arthritis. Hereinbelow, lameness is referred to by theexpression lameness with an osseous, articular or osteoarticularcomponent. It should be understood, however, that the osseous, articularor osteoarticular component can be present alone or combined with amuscular component and/or with a vascular component.

[0010] Lameness with an osseous, articular or osteoarticular componentappear in particular during osteoarthrosis, osteochondrosis, naviculardisease or enthesopathy of the bony insertions of the tendons, of theligaments or of the aponeurosis.

[0011] Among the factors which can bring about lameness with an osseous,articular or osteoarticular component, mention may be made of constantand/or intense mechanical stresses on the locomotor apparatus. In thecase of a person or animal unprepared for physical exercise, theintensity of the mechanical stress capable of bringing about lamenessmay be relatively low.

[0012] In contrast, in the case of a person or animal prepared forphysical exercise, lameness will appear when subjected to a mechanicalstress whose force or repetitive nature exceeds the resistancecapacities of the limbs. Certain animal species are more particularlyinclined to develop lameness with an osseous, articular and/orosteoarticular component. This is especially the case for equidaeanimals.

[0013] In point of fact, in horses, the locomotor apparatus is stressedmore frequently than it is in other animal species, either duringsporting competitions or when the horse is used by people as a mount. Inthis animal species, lameness represents one of the main clinicalconditions requiring veterinary consultation. Their clinical descriptionis well known; a fairly exhaustive review on this subject is presentedin the book “Les boiteries du cheval” [Lameness in horses] edited by O.R. Adams (published by Maloine, 1990). Lameness with an osseous,articular or osteoarticular component are the most common; descriptionshave especially been given in the art for navicular disease or horsepodotrochlear syndrome, bone spavin or osteoarthrosis of the distalstage of the tarsus in horses, horse osteochondrosis and enthesopathy ofthe bony insertions of the tendons, of the ligaments or of theaponeurosis in horses.

[0014] Thus, the invention relates to a process for treating lamenesswith an osseous, articular or osteoarticular component, comprising theadministration, to a person or to an animal (for example a horse) notsuffering from fractures or from arthritis, of a bisphosphonic acidderivative.

[0015] The bisphosphonic acid derivatives which can be used in thecontext of the invention have the general formula:

[0016] in which:

[0017] R₁ represents a hydrogen atom, a halogen atom, a hydroxyl, anamino, a mono(C₁-C₄)alkylamino or a di (C₁-C₄) alkylamino;

[0018] R₂ represents a halogen atom, a linear alkyl comprising from 1 to5 carbon atoms which is unsubstituted or substituted with a group chosenfrom a chlorine atom, a hydroxyl, an amino, a mono (C₁-C₄) alkylamino, adi (C₁-C₄) alkylamino; a (C₃-C₇) cycloalkylamino,

[0019] or R₂ represents a phenoxy, a phenyl, a thiol, a phenylthio, achlorophenylthio, a pyridyl, a pyridyl-methyl, a1-pyridyl-1-hydroxymethyl, an imidazolylmethyl or a 4-thiomorpholinyl.

[0020] The salts of these compounds with pharmaceutically acceptableinorganic or organic acids or bases can also be used in the context ofthe invention. Examples of salts with acids are hydrochloride,hydrobromide, sulphate, acetate, hydrogensulphate, dihydrogenphosphate,methanesulphonate, methylsulphate, maleate, fumarate, sulphonate,2-naphthalenesulphonate, glycolate, gluconate, citrate, isethionate,benzoate, salicylate, ascorbate, tartrate, succinate, lactate,glutarate, toluenesulphonate and ascorbate. As examples of salts withinorganic or organic bases, mention may be made of ammonium salts oralkali metal salts such as, for example, sodium salts.

[0021] The hydrates of these compounds can similarly be used accordingto the invention.

[0022] These compounds are described in particular in EP 623,347.

[0023] Among these bisphosphonic acid derivatives, mention may be madein particular of the following compounds:

[0024] 1-hydroxyethylidenebisphosphonic acid, whose internationalnonproprietary name is etidronic acid, and its sodium salts;

[0025] 2-pyrid-2-ylethylidenebisphosphonic acid, whose internationalnonproprietary name is piridronic acid, and its sodium salts;

[0026] dichloromethylenebisphosphonic acid, whose internationalnonproprietary name is clodronic acid, and its sodium salts;

[0027] 3-amino-1-hydroxypropylidenebisphosphonic acid, whoseinternational nonproprietary name is pamidronic acid, and its sodiumsalts;

[0028] 4-amino-1-hydroxybutylidenebisphosphonic acid, whoseinternational nonproprietary name is alendronic acid, and its sodiumsalts;

[0029] 6-amino-1-hydroxyhexylidenebisphosphonic acid and its salts;

[0030] phenoxymethylenebisphosphonic acid and its salts;

[0031] thiomorpholinomethylenebisphosphonic acid and its salts;

[0032] 4-chlorophenylthiomethylenebisphosphonic acid, whoseinternational nonproprietary name is tiludronic acid, and itspharmaceutically acceptable salts, in particular the disodium salt;

[0033] 1-hydroxy-2-(3-pyridyl)ethylidenebisphosphonic acid, whoseinternational nonproprietary name is risedronic acid, and its sodiumsalts;

[0034] 1-hydroxy-2-(2-imidazolyl)ethyl-1,1-bisphosphonic acid and itssalts;

[0035] (cycloheptylamino)methylenebisphosphonic acid and its salts;

[0036] 2-hydroxyethylidene-2-(3-pyridyl)-1,1-bisphosphonic acid and itssodium salts.

[0037] According to the present invention, the administration oftiludronic acid and of its pharmaceutically acceptable salts, inparticular the disodium salt, or of its hydrates is particularlypreferred.

[0038] Bisphosphonic acid derivatives are known to inhibit boneresorption and to decrease the activity of osteoclasts, as is found inparticular in the following articles:

[0039] “Diphosphonates inhibit hydroxyapatite dissolution in vitro andbone resorption in tissue culture and in vivo”, Fleisch H., Russell R.,Francis M., Science, 1969, 165, 1262-1264

[0040] “Two modes of action of bisphosphonates on osteoclasticresorption of mineralized matrix”, Boonekamp P. M., Van Der Wee-Pals L.J. A., Van Wijk-Lennep, Thesing C. W., Bijvoet O. L. M., Bone Miner.,1986, 1, 27-39

[0041] “Dichloromethylene bisphosphonate (Cl₂MBP) inhibits boneresorption through injury to osteoclasts that resorb CIMBP coated bone”,Flanaghan A. M., Chambers T. J., Bone Miner., 1989, 6, 33.

[0042] Many bisphosphonic acid derivatives are in development or arealready marketed in human medicine in the treatment of bone complaints.A review of the therapeutic uses of these derivatives is presented inthe book “Bisphosphonate on bones” edited by Bijvoet O. L. M., FleischH. A., Canfield R. E. and Russell R. G. G. (Elsevier Science BV, 1995)The main uses concern the treatment of bone complaints such as Paget'sdisease or osteoporosis. The other uses usually described are directedtowards the treatment of malignant hypercalcaemia, bone tumours or bonemetastasis. It has also been possible to demonstrate theanti-inflammatory activity of certain bisphosphonic acid derivatives ina model of arthritis in rats, induced by injection of mycobacterium.

[0043] However, the authors are unaware of any studies demonstrating theanti-inflammatory activity of these bisphosphonic acid derivatives inpathologies other than arthritis or more generally in other species (andfor example in man). More recently, the value of certain bisphosphonicacid derivatives in improving the repair of fractures has beendescribed. Reference will be made in particular to EP 600,834 or U.S.Pat. No. 5,488,041.

[0044] In another field, the use of bisphosphonic acid derivatives isalso described in the diagnosis of certain bone complaints byscintigraphy. An example of such a use is reported by Keegan K. G.,Wilson D. A., Lattimer C. L., Twardock A. R., Ellersieck M. R. (Am. J.Vet. Res., 1996, 57, 415-421) in the scintigraphic evaluation of^(99m)Tc-methylene diphosphonate labelling of the navicular region inhorses with lameness localized on the foot. However no mention is madeof the clinical benefit provided by binding the bisphosphonic acidderivative in the bones of the palmar region.

[0045] The medical treatments most usually prescribed for lameness aredirected towards pain relief; this is the case, for example, fortreatments with non-steroidal anti-inflammatory medicines. However,these treatments are unsatisfactory since they do not treat the injurieswhich are the cause of the inflammation. Their efficacy is moreoverlimited to the period of administration, since the beneficial effects ofthe anti-inflammatories disappear as soon as treatment has ended. Restis also often recommended to allow the region of the locomotorapparatus, which is the cause of lameness, to return to a normal state.More specifically, in horses, the use of orthopaedic shoes isrecommended. Even more particularly, in this animal species, the use ofcompounds which modify vascularization in the navicular region isrecommended in the treatment of navicular disease; it is for theseconditions that isoxsuprine, a vasodilator, is prescribed by Gabriel A.,Caudron I., Serteyn D., Collin B. in “Syndrome naviculaire: anatomie,étiopathogénie, diagnostic, traitement” [Navicular syndrome: anatomy,aetiopathology, diagnosis and treatment], Ann. Med. Vet., 1994, 138,309-330).

[0046] Surprisingly, it has been found that bisphosphonic acidderivatives are useful in the treatment of lameness with an osseous,articular or osteoarticular component. It has been shown, entirelyunexpectedly, that the use of these derivatives allows a significant andlong-lasting improvement in the clinical signs of lameness, or evencuring of lameness, even beyond the treatment period, and without anyincrease in bone density being detectable by radiological examination.

[0047] Thus, the beneficial effects observed are not thought to belinked to the bone resorption-inhibiting activity of the bisphosphonicacid derivatives.

[0048] Such medicines can be used in human medicine and in veterinarymedicine.

[0049] They can be administered via various routes of administration,for example parenterally, orally, rectally, intra-articularly,cutaneously, transcutaneously or transdermally.

[0050] The mode of administration of such medicines is determineddepending on the species treated, age, weight and the severity of thepathology.

[0051] The administration rhythm can consist of a single administrationor repeated administrations. In the case of repeated administrations,the treatment can be administered continuously or intermittently. When acontinuous treatment is chosen, the preferred administration rhythm maybe from a single daily administration to 3 daily administrations over aperiod which can range from a few days to a few months. When anintermittent treatment is chosen, one of the following administrationrhythms may be adopted: an administration every 2 or 3 days or a weekly,bimonthly or monthly administration over periods which can range from afew weeks to a few months.

[0052] The concentration of the medicine, in terms of bisphosphonic acidderivative, depends on the activity and on the duration of action ofthis derivative, the mode of administration, the age, the weight, thesex, the importance of the desired effect, the intended species or, forcertain animal species, the race.

[0053] For liquid preparations for parenteral or oral use, theconcentration of the medicine, in terms of bisphosphonic acidderivative, can be between 0.001% and 90% as a weight/volume ratio. Forpreparations intended for the oral route, it can be between 0.001 mg and10 g per dosage unit.

[0054] The medicine can also be in the form of an implant.

[0055] The doses during each administration of the medicines preparedaccording to the present invention, expressed relative to the bodyweight, can range between 0.001 mg/kg and 100 mg/kg.

[0056] For example, doses of from 0.01 mg/kg/week to 1 mg/kg/week oftiludronic acid or of one of its salts may be administered intravenouslyto horses.

[0057] For an oral administration, the pharmaceutical composition whichcan be used according to the invention may be in the form of a tablet, agelatin capsule, a powder, a granule, drops or any other form which canbe administered orally.

[0058] The composition which can be used according to the invention mayalso contain ingredients usually used in pharmacy for the preparation oforal forms. Thus, the said composition can contain a disintegrationagent, a flow agent, a lubricant and any excipient of suitable mass.

[0059] Lactose, cellulose or starches can be used as mass excipient.Stearic acid, magnesium stearate, L-leucine or, for example, glyceryltribehenate can be used as lubricant. Sodium carboxymethylstarch,crosslinked sodium carboxymethylcellulose or, for example, crosslinkedpolyvinylpyrrolidone can be used as disintegration agent. Pure silica orcolloidal silicon dioxide can be used as flow agent.

[0060] The present invention also relates to rapidly dissolving oralforms and to effervescent oral forms obtained by adding an effervescentcouple to the composition according to the invention. Tartaric acid andsodium bicarbonate or citric acid and sodium bicarbonate can be used aseffervescent couple.

[0061] The invention also relates to the use of rapidly dissolvingtablets, effervescent tablets and tablets covered with a coating. Acomposition containing sodium lauryl sulphate according to Europeanpatent EP 336,851 is particularly suitable.

[0062] For rectal administration, use is made of suppositories which areprepared with binders that melt at rectal temperature, for example cocoabutter or polyethylene glycols.

[0063] The preparations for injection are prepared by mixing one or morebisphosphonic acid derivatives with a pH regulator, a buffer agent, asuspension agent, a solubilization agent, a stabilizer, a tonicity agentand/or a preserving agent, and by converting the mixture into anintravenous, subcutaneous or intramuscular injection, according to astandard process. Where appropriate, the preparations for injection canbe lyophilized according to a standard Process.

[0064] Examples of suspension agents include methylcellulose,polysorbate-80, hydroxyethylcellulose, acacia, powdered gum tragacanth,sodium carboxymethylcellulose and polyethoxylated sorbitan monolaurate.

[0065] Examples of solubilizing agents include castor oil solidifiedwith polyoxyethylene, polysorbate-80, nicotinamide, polyethoxylatedsorbitan monolaurate, macrogol and the ethyl ester of castor oil fattyacid.

[0066] In addition, Examples of the stabilizer includes sodium sulphite,sodium metasulphite and ether, while examples of the preserving agentincludes methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid,phenol, cresol and chlorocresol.

[0067] An example of a tonicity agent is mannitol.

[0068] During the preparation of the solutions or suspensions forinjection, it is desirable to take care to ensure that these areisotonic with the blood.

EXAMPLE 1

[0069] A clinical study was carried out to evaluate the effects of atreatment with disodium tiludronate on horses which develop lamenessduring navicular disease (also known as podotrochlear syndrome).

[0070] The study was carried out on 24 horses, the diagnosis of thenavicular disease causing lameness being based on the followingcriteria:

[0071] local signs in the palmar region: heat, swelling, pain

[0072] functional signs of limping graded on a scale from 0 (no sign oflimping) to 4 (trouble in bearing weight when at rest and/or in motionand difficulty in moving around)

[0073] a functional test of locomotion after flexing the palmar region,also assessed on a scale from 0 (locomotion not changed by flexure) to 4(start of suppression of bearing weight)

[0074] a radiological examination to assess radiological signs in thepalmar region qualitatively.

[0075] To be included, the animal had to show no signs or lesions ofseptic arthritis, or any fractures of the bones in the palmar region.Also, it needed to have not received an injection for anti-inflammatorytreatment in the joints of the palmar region.

[0076] The wearing of an orthopaedic shoe was not contra-indicated sincemost of the animals had been laming for several weeks and were alreadywearing a shoe of this type.

[0077] All the animals received, as a single treatment, disodiumtiludronate in the form of an injectable solution administeredintravenously at a dose of 0.1 mg/kg, at a weekly administration ratefor 6 to 10 weeks. The first day of treatment corresponds to D0.

[0078] To assess the effects of the treatment, the animals were reviewed1 month after D0 (M1), 2 months after D0 (M2) and 6 months after D0(M6). The effects of the treatment were assessed with regard to:

[0079] the local signs, the functional signs and the test of locomotionafter flexure as defined during inclusion of the animal into the test aradiological examination to assess the change in the radiological signs

[0080] an assessment of the resumption of the animal's sportingactivity.

[0081] Taking all these criteria into account allows the horse to beplaced in one of the following categories after the 3 controlexaminations at M1, M2 and M6:

[0082] “very favourable” category: absence of local signs, grade 0 forthe functional test and signs; the animal resumed activity comparable tothat in which it was engaged before limping

[0083] “favourable” category: the local signs are very much attenuated,the functional signs have been improved by 1 or 2 degrees, the horse isready to resume physical activity comparable to that in which it wasengaged before limping

[0084] “average” category: persistence of local signs, functional signsimproved by 1 degree; persistence of a locomotor difficulty preventingthe animal from resuming normal physical activity

[0085] “mediocre” category: persistence of the local signs, noimprovement in the functional signs

[0086] “poor” category: no improvement in the local or functional signs,or even worsening of the local signs and of the functional signs.

[0087] The table below summarizes the effects of the treatment(expressed as a percentage of animals present in each category):Examination Examination Examination Category at M1 at M2 at M6 Veryfavourable 8% 26% 18% Favourable 46%  43% 46% Average 38%  26% 27%Mediocre 4%  5%  9% Poor 4%  0%  0%

[0088] These results demonstrate the beneficial effects ofadministration of the bisphosphonic acid derivative, by revealing achange in kinetics of lameness. The benefit of the treatment is optimal2 months after administration of the treatment is started. The treatmentleads to a complete recovery for a quarter of the animals at the end ofits administration. The benefit of the treatment is maintained in anentirely satisfactory manner beyond the treatment period.

[0089] Radiological examination did not reveal any change in kinetics ofthe pathological radiological signs in the palmar region.

EXAMPLE 2

[0090] A clinical study was carried out in order to evaluate the effectsof a treatment with disodium tiludronate on horses which developlameness during bone spavin (which is osteoarthrosis of the distal stageof the tarsus).

[0091] The test procedure and the clinical monitoring of the animalswere the same as those described in Example 1, except that the local,functional and radiological signs were assessed in the region of thehock.

[0092] 5 horses were included in this test.

[0093] The results obtained were as follows (expressed as a percentageof animals present in each category): Examination ExaminationExamination Category at M1 at M2 at M6 Very favourable 0% 40%  40%Favourable 40%  60%  20% Average 60%  0% 20% Mediocre 0% 0%  0% Poor 0%0% 20%

[0094] The change in lameness induced by bone spavin is favourable tovery favourable in most of the animals after treatment. The persistenceof the beneficial effects is also very satisfactory.

EXAMPLE 3

[0095] A clinical study was carried out to evaluate the effects of atreatment with disodium tiludronate on horses which develop lamenessassociated with bone lesions in the form of sub-chondral cysts duringosteochondrosis.

[0096] The test procedure and the clinical monitoring of the animalswere the same as those described in Example 1, except that the local,functional and radiological signs were evaluated in the joints affectedby osteochondrosis.

[0097] 5 horses were included in this test.

[0098] The results obtained were as follows (expressed as a percentageof animals present in each category): Examination ExaminationExamination Category at M1 at M2 at M6 Very favourable 40% 20% 60% Favourable  0% 40% 0% Average 40% 20% 0% Mediocre  0%  0% 40%  Poor 20%20% 0%

[0099] These results demonstrate the clinical benefit afforded byadministration of the bisphosphonic acid derivative on the treatment oflameness associated with bone lesions during osteochondrosis.

EXAMPLE 4

[0100] A clinical study was carried out to evaluate the effects of atreatment with disodium tiludronate on horses which develop lamenessduring enthesopathy of the insertion of the tendons and the ligaments.

[0101] The test procedure and the clinical monitoring of the animalswere the same as those described in Example 1, except that the local,functional and radiological signs were evaluated in the region of thetendon or ligament insertions at the source of lameness.

[0102] 6 horses were included in this test.

[0103] The results obtained were as follows (expressed as a percentageof animals present in each category): Examination ExaminationExamination Category at M1 at M2 at M6 Very favourable  0% 0% 40%Favourable 50% 67%  40% Average 33% 33%   0% Mediocre 17% 0% 20% Poor 0% 0%  0%

[0104] These results demonstrate the clinical benefit afforded byadministration of the bisphosphonic acid derivative on the treatment oflameness caused by insertion enthesopathies.

1. Process for treating lameness with an osseous, articular orosteoarticular component, comprising the administration, to a human orto an animal not suffering from arthritis or from fractures, of aneffective amount of a bisphosphonic acid derivative of formula:

in which: R₁ represents a hydrogen atom, a halogen atom, a hydroxyl, anamino, a mono(C₁-C₄)alkylamino or a di (C₁-C₄) alkylamino; R₂ representsa halogen atom, a linear alkyl comprising from 1 to 5 carbon atoms whichis unsubstituted or substituted with a group chosen from a chlorineatom, a hydroxyl, an amino, a mono(C₁-C₄)alkylamino or a di(C₁-C₄)alkylamino; a (C₃-C₇) cycloalkylamino, or R₂ represents aphenoxy, a phenyl, a thiol, a phenylthio, a chlorophenylthio, a pyridyl,a pyridyl-methyl, a 1-pyridyl-1-hydroxymethyl, an imidazolylmethyl or a4-thiomorpholinyl, of one of its pharmaceutically acceptable salts or ofone of its hydrates.
 2. Process according to claim 1, for treating ananimal belonging to the equidae family.
 3. Process according to claim 1,for treating a horse.
 4. Process according to claim 1, for treatinglameness which appear during osteoarthrosis, osteochondrosis, naviculardisease or enthesopathy of the bony insertions of the tendons, of theligaments or of the aponeurosis.
 5. Process according to claim 1,comprising the administration of from 0.001 mg/kg to 100 mg/kg of bodyweight of the said bisphosphonic acid derivative.
 6. Process accordingto claim 1, for treating limps in horses, comprising the intravenousadministration of from 0.01 mg/kg/week to 1 mg/kg/week of tiludronicacid or of one of its pharmaceutically acceptable salts.
 7. Processaccording to claim 1, comprising the oral administration of the saidbisphosphonic acid derivative.
 8. Process according to claim 1,comprising the parenteral administration of the said bisphosphonic acidderivative.
 9. Process according to claim 1, comprising theadministration of the said bisphosphonic acid derivative in the form ofan implant.
 10. Process according to claim 1, in which the saidbisphosphonic acid derivative is selected from:1-hydroxyethylidenebisphosphonic acid and its sodium salts;2-pyrid-2-ylethylidenebisphosphonic acid and its sodium salts;dichloromethylenebisphosphonic acid and its sodium salts;3-amino-1-hydroxypropylidenebisphosphonic acid and its sodium salts;4-amino-1-hydroxybutylidenebisphosphonic acid and its sodium salts;6-amino-1-hydroxyhexylidenebisphosphonic acid and its salts;phenoxymethylenebisphosphonic acid and its salts;thiomorpholinomethylenebisphosphonic acid and its salts;4-chlorophenylthiomethylenebisphosphonic acid and its salts;1-hydroxy-2-(3-pyridyl)ethylidenebisphosphonic acid and its sodiumsalts; 1-hydroxy-2-(2-imidazolyl)ethyl-1,1-bisphosphonic acid and itssalts; (cycloheptylamino)methylenebisphosphonic acid and its salts;2-hydroxyethylidene-2-(3-pyridyl)-1,1-bisphosphonic acid and its sodiumsalts.
 11. Process according to claim 10, in which the saidbisphosphonic acid derivative is4-chlorophenylthiomethylenebisphosphonic acid.